In response to RFA DA-08-009: HIV-1 and Host Genetics in Drug Using Populations and Model Organisms, the overarching goal of this project is to identify and characterize genetic determinants of HIV-1 susceptibility and resistance in large samples of African American and European American injection drug users (IDU) by conducting: 1) a case/control genome-wide association (GWA) study of HIV-1 infection (positive / negative); 2) a case-only GWA study of viral load among HIV+ IDUs. Host genetic studies hold out the promise of identifying genetic variants that influence the human response to HIV-1. Such variants would help determine aspects of the human response to HIV-1 that may be the best targets for developing a vaccine against HIV-1. Progress is being made in genetic studies of HIV-1 infection. However, nearly all reported findings are from candidate gene studies, which explain only a fraction of the variability of HIV-1 infection. The limited availability of large relevant cohorts for genetic study, the absence of African Americans from current genetic studies despite the disproportionate HIV burden in this community, and the limited attention to the IDU population limit the field's ability to identify genetic variants affecting HIV-1 infection and strongly argue for the need to conduct large-scale GWA studies of HIV-1 infection phenotypes. The proposed study will use existing samples and data from Urban Health Study (UHS), the longest- running study of street-recruited IDUs in North America to achieve the following aims: Aim 1: To evaluate genetic associations for HIV-1 susceptibility/resistance in HIV+ cases and high risk HIV negative controls among African American and European American IDUs. Separate GWA analyses will be conducted among African American and European American IDUs (n= 5,583 and 3,864, respectively). Aim 1a: To quantify and balance the level of HIV risk among HIV positive cases and high-risk HIV negative controls using Propensity Score Methods in preparation for GWA studies. Aim 1b: To explore gene by HIV risk interactions for top SNPs associated with HIV-1 status. Aim 2: To evaluate genetic associations of viral load among African American and European American HIV positive IDUs. Aim 3: To replicate primary findings in Center for HIV Vaccine Immunology (CHAVI) cohorts. PUBLIC HEALTH RELEVANCE: This study of injection drug users will identify genes associated with HIV-1 infection and HIV viral load, the latter being an important predictor of disease progression and development of AIDS. This will be the first genetic study to include African Americans, a group who suffers a disproportionate HIV burden in the United States. The results of this study may identify important biological pathways and targets for developing a vaccine against HIV-1.